Safety and Effect of The HDAC Inhibitor Panobinostat on HIV-1 Expression in Patients on Suppressive HAART (CLEAR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.

The purpose of this study is to assess the safety and ability of panobinostat to re-activate HIV transcription in latently infected CD4+ T-cells among HIV-infected patients on stable antiretroviral therapy

Several therapeutic strategies are considered in HIV-cure related research. One approach is to exploit the ability of histone deacetylase (HDAC) inhibitors to reactivate HIV-1 expression in latently infected cells in the presence of HAART.

This is an investigator initiated single-group, non-randomized interventional phase I/II trial designed to evaluate the safety and ability of oral panobinostat to activate HIV-transcription in latently infected CD4+ T-cells of HIV-infected patients on suppressive HAART. The study will enrol 16 patients. Each subject will be used as his/her own control in a before-after design: endpoints measured after study intervention will be compared to baseline for each subject.

The main study will comprise three phases:

A pre-treatment screening/observation phase of 4 weeks (weeks 0-4)

A treatment phase of 8 weeks (weeks 4-12), where 20 mg panobinostat will be administered orally on days 1, 3, and 5 (TIW) every other week (QOW) while maintaining background HAART (co-therapy)

A post-treatment follow-up phase of 24 weeks (weeks 12-36) to evaluate the effect of study treatment

Study participants will be reviewed 13 times during the course of study treatment and follow-up. Blood will be drawn for HIV viral load assessments, CD4 cell counts, biochemistry, hematology and additional immunological and virological analyses. An electrocardiogram of the heart (ECG) will be taken at screening, day 10 and 24 post treatment initiation.

The safety and tolerability of panobinostat will be evaluated based on physical exams, laboratory tests and questions about any problems patients may have experienced during the study. A pre-specified schedule based will guide dose modification in case of unacceptable adverse effects.

Change from baseline in HIV transcription in latently infected CD4+ T-cells as measured by copies of unspliced HIV-RNA in the CD4+ T-cells of HIV-infected patients on suppressive HAART [ Time Frame: Day 1 (before study drug and 2 hours after first dose), Day 2, 5, 10, 15, 24, 29, 38, 43, 52 ]

Secondary Outcome Measures
:

Change from baseline in the size of the latent HIV-reservoir as measured by copies of proviral HIV-DNA per 10⁶ CD4+ T-cells [ Time Frame: 12 and 32 weeks after initiation of study treatment ]

Change from baseline in the frequency of cells latently infected with replication competent HIV expressed as infectious units per million (IUPM) [ Time Frame: 12 weeks after initiation of study treatment ]

During an optional HAART-interruption study (if performed, see below): 1) Time to viremia >1000 copies/ml; 2) Time to meet criteria to restart HAART [ Time Frame: To be performed upon completion of 32 weeks follow-up based on the below specified criteria ]

Upon completion of the study, subjects may be invited to participate in an additional observational study in which HAART will be interrupted to evaluate the effect of study treatment on virological control. Enrolment into this study is optional and conditioned by the following criteria pertaining to the effect of study treatment on the latent HIV-1 reservoir:

Significant increase in unspliced HIV-RNA during in accordance with the primary endpoint measure

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Documented HIV-1 infection

Age >18 years

HIV-1 plasma RNA <50 copies/ml for at least 2 years with at least 2 viral load measures per year. Episodes of a single HIV plasma RNA 50-199 copies/ml will not exclude participation if the subsequent HIV plasma RNA was <50 copies/ml

Current or recent gastrointestinal disease that may impact the absorption of the investigational drug

Any gastrointestinal surgery that could impact upon the absorption of the investigational drug

Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate compliance with study therapy

Patient has the following laboratory values within 3 weeks before starting the investigational drug (lab tests may be repeated, as clinically indicated, to obtain acceptable values before failure at screening is concluded but supportive therapies are not to be administered within the week prior to screening tests for ANC or platelet count)

History of malignancy or transplantation, including skin cancers or Kaposi sarcoma

History of diabetes mellitus

Use of a protease inhibitor

Receipt of immunomodulating agents, immunization or systemic chemotherapeutic agents within 28 days prior to study entry

Use of an agent definitely or possibly associated with effects on QT intervals within 2 weeks of screening

ECG at screening that shows QTc >450 msec when calculated using the Fridericia formula from either lead V3 or V4

Known resistance to >2 classes of ART

Known hypersensitivity to the components of panobinostat or its analogues

Current use of sodium valproate or other HDAC inhibitor

Women who are pregnant or breastfeeding, or with a positive pregnancy test during screening or Women of Child Bearing Potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception (according to the Danish Medicines Agency guidelines) to avoid pregnancy for the entire study period and for at least 4 weeks before and 4 weeks after study treatment

Males or females who are unwilling or unable to use barrier contraception during sexual intercourse for the entire study period, including at least 4 weeks before, 4 weeks after study treatment, and when plasma HIV-RNA is detectable using standard assays